Method and perparations having effect against allergic symptoms

ABSTRACT

A method of making a preparation having effect against allergic symptoms, more particularly a preparation which has proved to be effective for therapeutic and prophylactic relief or prevention of symptoms associated eith allergic rhinitis, asthmatic conditions and other allergic conditions, such as allergic conjunctivitis, urticaria, or insect or plant stings, and in which fresh, newly harvested plants of the species Artemisia or other davanon containing plants are boiled in water (1), whereby water steam and volatile essential oils are given off, said oils are collected (2), the residue green mass is heated in water to allow for hydrolysis of the chemical components (3) which are extracted with alcohol (4) and are mixed with the previously extracted essential oils. The alcohol extract could be exchanged for an extract of another plant (e.g. thyme or chamomile) containing spasmolytic or antiallergic components. The invention also relates to a preparation made according to the method.

[0001] The present invention relates to a method for making preparationshaving effect against allergic symptoms, more particularly a preparationwhich has proved to be effective for therapeutically andprophylactically relieving discomforts connected to allergic rhinitisand asthmatic affections, for instance exercise induced or airwayobstruction asthma bronchiale, allergic conjuctivitis urticaria andother types of allergic symptoms or disorders. The preparation is anature-cure medicine which can be used for self medication and can beadministered as a nasal spray, or by inhalation in airways by spray orpowder. The preparation can also be prepared for topical administrationin eyes or on skin or on mucous membrane. It is also possible to add thepreparation to various kinds of foods. The preparation has been shown togive a good therapeutic as well as prophylactic effect for said allergicconditions.

[0002] Surprisingly it has been shown that certain substances which havea good effect against different allergic affections, including asthmaticupper airways conditions, can be extracted from plants. It has also beenshown that the preparations made according to the invention have rapidonset and prolonged effect. Importantly, the effect can be obtainedalready within two minutes. The therapeutic effect remains for aconsiderable period of time after the preparation has been administered.

[0003] The plants which are relevant in this connection are certainspecies of Artemisia, in particular Artemisia abrotanum (southernwood)and other davanon containing plants, A. pallens, A. lerchiana, A.thuscula, A. rehan, A. persica, A. glabella, and A. rupestris, but alsoLantana camara and Tanacetum vulgare. A part of the extract can also besubstituted by extracts from other plants having spasmolytic activity,e.g Thymus vulgaris or Chamomilla recutita.

[0004] Certain problems have appeared in the manufacture of thepreparation. Previously it has been common procedure that the plant wasdried, and that an extract is prepared from the dried plant. This doesnot, however, work in the present case. It has also been shown that theplant must be relatively young and that the preparation is made fromfresh plants which have been harvested (in Scandinavian climate) duringMay-July. At a later harvest the plant grows woody, it becomes difficultto extract the plant to obtain the desired preparation, and it gives abitter taste. This depends on the fact that the content of essentialoils in the green mass of fresh plants is higher than that of driedplants, and that the composition of different essential oils in thefresh green mass is different from that of more woody plants. During thecourse of the growth there is a change of the essential oil fractionwhich is unfavorable for this purpose. While the total content ofessential oils is relatively constant, the content of the valuable oilcomponent davanon decreases whereas the content of 1.8-cineol increases.Attempts have been made to use eucalyptus oil as the oil fraction of thepreparation, eucapyptus oil contains a high amount of 1.8-cineol whichis the main component of the oil from southernwood during late summer.This preparation has been shown to be marginally effective. It can beestablished that the presence of the oil component davanon, on thecontrary, strongly improves the activity of the preparation. Whilepreparations from southernwood having a high content of davanon givesfull effect within two minutes, a corresponding product in which the oilhas been substituted by eucalyptic oil, exhibits only about 50% of theeffect. Tests also have been made in which the essential oil part hascompletely been substituted by davanon.

[0005] It has also been shown that an extract of only the green mass ofthe plant does not give the desired result, also the extraction and useof only the essential oils of the plant does not give the desiredresults. On the contrary, if, firstly, the essential oils of the plantsare separated from the plant by steam distillation whereupon theremaining green mass is extracted with alcohol, and the essential oilsand the alcohol extracts are mixed, an effective product is obtained.

[0006] 100 g dry plant material of the entire plant southernwood,without the root, contains the following flavonols:

[0007] 7 mg Casticin

[0008] 5 mg Centaureidin

[0009] 5 mg Quercitin 3.4-dimethyl ether

[0010] 5 mg Quercetin 3.7-dimethyl ether

[0011] Several variants of the above indicated preparation have beentested and it was shown that the amount of flavonols can vary withincertain limits, even if the above mentioned values are considered togive optimum effects:

[0012] Casticin 1-8 mg

[0013] Centaureidin 1-7 mg

[0014] Quercetin 3.4-dimethyl ether 0.5-8 mg

[0015] Quercetin 3.7-dimethyl ether 0.5-8 mg

[0016] It is not clear why a good effect of a preparation of theessential oils added to an alcohol extract of the residue green mass isobtained, but the following are hypotheses:

[0017] The plant contains flavonol glycosides and it may be that theflavonol fraction of the plant needs to be deglycosylated in order tobecome active;

[0018] The oil fraction obtained from younger plants, harvested in thebeginning of the summer, is more active than oil from plants harvestedlater;

[0019] The preparation should be made from fresh green mass since theoil fraction of the plant contains volatile components which get lostwhen the plant is dried;

[0020] There is a synergistic effect between the oil fraction and theflavonol fraction;

[0021] It is possible that the essential oil prepare the mucousmembranes so that the flavonols can enter the cells and thereby inducetheir effect.

[0022] Preferred oil contents are between 0.2 ml and 0.0005 ml per 20 mlof the product.

[0023] A further problem in producing the preparation is that most ofthe actual Artemisia species, e.g. southernwood, can not be cultivatedby seed cultivation, but the cultivation has to be made by cuttingbreeding. This gives, however, the advantage that the grown materialbecomes a clone of a so called chemotype, having a defined chemicalcomposition. A special clone has been selected and used in the clinicaltests. This clone does not produce thujone when grown under Swedishclimate conditions.

[0024] In a preliminary clinical experimental study, in which seven testpersons were subjected to, among other things, horsehair and cat,allergic symptoms as mucous swelling and running nose were observed. Thepreparation made according to the above was administered:

[0025] 1. Before provocation with allergen for instance from dog andcat; no allergic symptoms were observed;

[0026] 2. After provocation of allergic symptoms with horsehair; thesymptoms of rhinitis and running nose disappeared with two minutes;

[0027] 3. In subjects with exercise induced asthmatic symptoms, inducedby for example long distance running; the symptoms disappeared and thetest person was free from symptoms within 5-8 minutes;

[0028] 4. For patients with allergic symptoms from the eyes, so calledconjunctivitis, also these symptoms disappeared within the same timeframe.

[0029] 5. In patients with inflammation on mucous membranes, such assores on the lip or other inflammations such as gingiritis; substantialsymptom relief occurred.

[0030] In all cases in said preliminary study a full effect was quicklyobtained without any remaining symptoms. The only adverse effect thatcould be noted was a slight smarting pain of short duration in the nosewhile spraying the preparation.

[0031] The most important fields of use for the preparation according tothe invention can be considered to be exercise induced asthma, allergicrhinitis, allergic conjuctivitis, and urticaria. For these disorders ordiseases the preparation may very well be used for self medication. Thepreparation can also be used in the therapeutic as well as prophylacticmanagement of the above mentioned different conditions. The preparationhas also been demonstrated to have a good effect on insect stings frommany different types of insects like mosquitoes, gnats, wasps, bees,horse-flies etc.

[0032] The chemical composition of the plant has been documented invarious scientific investigations. Thus, the plant contains flavonols,which exhibit a spasmolytic effect in vitro, and terpenes like cineol(antiseptic and mucolytic compound) as well as davanon. The studiesmentioned above represent the first tests in which the preparation hasbeen used against allergic symptoms in vivo as well as in local ortopical pharmaceutical preparations.

[0033] Flavonols represent a group of well defined so called secondarymetabolites, which are found in most plants. The flavonols showvariations in the number of hydroxyl groups and in the degree ofmethylation. In the plants, the flavonols present are bound to sugarmolecules, but these products are hydrolyzed to liberate the freeflavonols during the extraction procedure.

[0034] Flavonols from southernwood can induce significant therapeuticeffects. Other Artemisia species may contain alternative flavonols thanthose from southernwood. It is, for instance, known that flavonols fromonion may inhibit the liberation of histamine, which might accentuatesymptoms in a variety of allergic disorders.

[0035] Importantly, the flavonol fraction by itself in southernwoodextracts does not induce any noticeable therapeutic effect in allergicconditions although such preparations may have a spasmolytic activity.Furthermore, the combination of southernwood oil and directly extractedfresh green mass does not have antiallergic effects either, nor doespreparations made from dried green mass and southernwood oil from driedplants elicit therapeutic effects in allergic conditions. Extracts fromfresh green mass combined with an oil fraction in which davanon is themain component, such as eucalyptus oil, shows a weak effect, however notto the extent as the therapeutic properties of the combination ofalcoholic extract from green mass of southernwood and southernwood oil.The essential oil from A. thuscula has been shown to exhibit aspasmolytic effect in the airways of guinea pigs. This effect isdependent on the content of davanon in the preparation.

[0036] In the accompanying drawing (sole figure) a flow chart is shownof a procedure to make a preparation from an Artemisia species like A.abrotanum (southernwood), having effect against allergic symptoms. Theprocess includes seven successive steps.

[0037] Step 1. Fresh southernwood, preferably harvested in the month ofJune or July (in Scandinavian climate) is boiled in water. Water andcertain volatile oils are distilled, as marked with the arrow in theaccompanying drawing.

[0038] Step 2. Water steam and oils are allowed to condense, whereby theessential oils become separated and are collected for later use.

[0039] Step 3. The pre-cooked green mass of step 1 is cooked in waterfor 5-60 minutes. By such cooking the composition is changed chemically,and the flavonol glycosides which are present in the plant arehydrolyzed to free flavonols and sugar.

[0040] Step 4. The green mass is dried, and thereafter extracted withalcohol. The free flavonols are dissolved in the alcoholic extract.

[0041] Step 5. In this step the essential oils, which were separated andcollected in step 2, are admixed into the alcoholic extract from step 4.

[0042] Step 6. The mixture of the essential oils from step 2 and thealcoholic extract from step 4 are diluted in water to an alcohol contentof about 25%, whereby a final product is obtained. A lower alcoholcontent reduces the solubility of the oil whereas a higher alcoholcontent is irritating to the mucosa

[0043] Step 7. The product from step 6 is further processed to provide asuitable preparation for e.g. topical use and then packed in a suitablepackage, for instance a spray container in order to make it possible tospray the preparation into the nose or the throat, use it in eye dropsor apply it topically to the skin, mucous membranes or teeth, oralternatively for use as an additive in food products or other products.

[0044] In the following examples there were used three differentextracts: F1, a concentrated extract containing 8 mg Casticin, 7 mgcentaureidin, 8 mg quercetin 3.4-dimetyl-ether and 8 mg quercetin3.7-dimethyl-ether; extract F2, which is the extract F1 diluted 1:4 with24% ehtanol; extract F3, which is the extact F1 diluted 1:10 with 24%ethanol.

EXAMPLES Example 1

[0045] Woman, 45 years old, nurse. The patient suffers from bronchialasthma under physical effort (jogging). The patient used a preparation,extract F1 according to the present invention (instead of Terbutalin(Bricanyl, Draco). The preparation contained 0,1 ml essential oil per 20ml alcohol. Full effect was reached within 2 minutes.

Example 2

[0046] The same patient used a preparation, extract F1 containing 0.2 mlessential oil per 20 ml alcohol. Full effect was obtained within 2minutes, only slightly or not better than in example 1 at differenttests.

Example 3

[0047] The same patient used a preparation, extract F1 containing 0.05ml essential oil per 20 ml alcohol. There was obtained somewhat lowereffect than in examples 1 and 2

Example 4

[0048] The same patient used a preparation, extract F2 containing 0.05ml essential oil per 20 ml alcohol. There was obtained somewhat lowereffect than in examples 1 and 2.

Example 5

[0049] A male, 48 years old, a district medical officer, allergic tocat, dog, pollen and horse, suffers from bronchial asthma under physicaleffort (jogging). Provocation by allergy agent followed by use ofallergic spray according to the invention after asthmatic attack. Thespray contained 0.1 ml essential oil per 20 ml alcohol, extract F1. Thepatient became free of symptoms within 2 minutes.

Example 6

[0050] Same patient as in example 5 was treated with a spray accordingto the invention containing 0.1 ml essential oil per 20 ml alcohol ofextract F2. The symptoms were reduced but the patient was not fullycures within 2 minutes.

Example 7

[0051] Same patient as in examples 5 and 6 was treated with a sprayaccording to the invention containing 0.1 ml essential oil per 20 mlalcohol of extract F3. Certain reduction of the pain was obtained within5 minutes but the patient was not fully cured.

Example 8

[0052] The same preparation as in example 5 was taken for preventivepurpose 5 minutes by the same person as in examples 5-7 beforeprovocation by allergens. Provocation was made by horsehair and by cat.No symptoms occurred.

Example 9

[0053] A male farmer, 54 years old suffers from allergic rhinitis anditching eyes when exposed to hay and air from swine stable. He has takenthe preparation according to the present invention instead ofterbutalin. A preparation was taken, for preventive purposes, containing0.05 ml of the essential oil per 20 ml of the alcohol extract of F1. Noproblems occurred within 2 hours.

Example 10

[0054] The same patient administered a preparation containing 0.05 ml ofthe essential oil according to the invention per 20 ml alcohol extractof F3. Slight problems occurred within 5 minutes.

[0055] The above examples thus show that the highest amount of oilshould not be higher than 0.2 ml per 20 ml of the product, and that thelowest value should not be less than 0.0005 ml per 20 ml of the product.

[0056] As also indicated above the lowest and the highest amount offlavonols ought to be

[0057] for Casticin 1-8 mg

[0058] for Centaureidin 1-7 mg

[0059] for Quercetin 3.4-dimethyl ether 0.5-8 mg

[0060] for Quercetin 3.7-dimethyl ether 0.5-8 mg

[0061] Flowchart:

[0062] 1.Fresh biomass boiled in water

[0063] 2. Condensation. Essential oils collected, water phase discarded.

[0064] 3. Boiling of residue green mass. Drying.

[0065] 4. Extraction of dry biomass with alcohol.

[0066] 6. Dilution of oil/extract mixture.

[0067] 7. Packing.

1. A method for making a preparation having effect against allergicsymptoms, more particularly a preparation which has proved to beeffective for therapeutic or prophylactic relief or prevention ofsymptoms associated with allergic rhinitis, asthmatic affections likeasthma bronchiale, allergic conjunctivitis, urticaria, insect or plantstings and other allergic conditions, characterized in that fresh, newlyharvested plants of the species Artemisia are boiled in water (1),whereby water steam and volatile essential oils are distilled, said oilsare collected (2), in that the residue green mass is heated in water toallow for hydrolysis of the chemical components (3), and extracting ofexisting chemical components of the plant, extracting said componentswith alcohol (4) and mixing the same with the essential oils obtained bythe steam distillation.
 2. A method according to claim 1, characterizedin that the water steam and the vaporized essential oils obtained fromthe first boiling process (1) are allowed to condense (2), and in thatthe oils which have collected on top of the water are separatedtherefrom.
 3. A method according to claim 1 or 2, characterized in thata secondary boiling (3) of the residue green mass is made under suchconditions that flavonol glycosides, which are present in the plant, arecleaved and deglycbsylated into free flavonols, which are extracted bymeans of alcohol (4).
 4. A method according to claim 3, characterized inthat the extraction with alcohol (4) is made so that non-volatilesubstances are extracted from the green mass.
 5. A method according toany of the preceding claims, characterized in that the mixture (5) ofthe alcoholic extract (4) and the collected essential oils is diluted toan alcohol content of 0-40%, preferably about 25%.
 6. A method accordingto claim 5, characterized in that the diluted mixture of the alcoholicextract (4) and the collected essential oils (2) are processed into andpacked as a nasal or throat spray or powder, or as a topical compositionfor use in eyes or on skin, on mucous membranes or teeth, or is used asan additive in other administration products.
 7. A preparation havingeffect against allergic symptoms and prepared according to any of thepreceding claims, characterized in that the preparation is obtained fromfresh, newly harvested plants comprising Artemisia species, inparticular Artemisia abrotanum (southernwood), or other danavoncontaining plants like A. davana, A, pallens, A. lerchiana, A. thuscula,A. rehan, A. persica, A. glabella, A. rupestris, Lantana camara andTanacetum vulgare, and comprising a mixture of volatile essential oilssteamed off from the plant in a first process step and non-volatile oilsand flavonols extracted in a second process step, or in which theethanol extract is substituted by substances from other plants withspasmolytic or antiallergic properties.
 8. A preparation according toclaim 7, characterized in that the preparation further comprises davanonand at least some portion of cineol.
 9. A preparation according to claim7 or 8, characterized in that the original plants consist of Artemisiaabrotanum (southernwood) or other davanon containing plants.